Vengeliene Valentina, Olevska Anastasia, Spanagel Rainer
Institute of Psychopharmacology, Central Institute of Mental Health, Faculty of Medicine Mannheim, Heidelberg University, Mannheim, Germany.
J Neurochem. 2015 Dec;135(6):1080-5. doi: 10.1111/jnc.13350. Epub 2015 Sep 22.
It is well known that the glutamatergic system plays a crucial role in alcohol addiction and especially in relapse-like behaviour. However, results of clinical studies on compounds that influence the activity of the glutamatergic system have been disappointing so far. The aim of our study was to establish treatment conditions under which the N-methyl-d-aspartate receptor (NMDAR) antagonist memantine may produce more reliable treatment effect with respect to alcohol relapse-like behaviour. For this purpose, male Wistar rats were trained to associate several discrete stimuli with ethanol delivery. Thereafter, half of the animals received a brief memory reactivation session followed by two administrations of 20 mg/kg of memantine, while the other half received the same treatment without memory reactivation. Afterwards, a cue-induced ethanol-seeking behaviour test was performed followed by repeated extinction sessions and a reacquisition test. Our data show that administration of memantine reduced responding on the ethanol-associated lever in a cue-induced ethanol-seeking test. This reduction did not depend on whether or not a memory reactivation session was introduced prior to memantine administration. Following extinction, however, reacquisition of ethanol self-administration was only impaired in the group where memantine was given after a short memory reactivation session, showing that this schedule of drug administration produced a long-lasting disruption of the association between the conditioned stimuli and the delivery of ethanol. In conclusion, we show that memantine disrupted the drug-cue association, which consequently interfered with relapse-like behaviour supporting the possibility that memantine is a treatment option for alcoholism. Our data supports the possibility that memantine is a treatment option for alcoholism. However, the effectiveness of this drug seems to lie in its ability to disrupt conditioned behaviours and should be given in conjunction with exposure to conditioned drug stimuli.
众所周知，谷氨酸能系统在酒精成瘾尤其是复发性行为中起着关键作用。然而，迄今为止，关于影响谷氨酸能系统活性的化合物的临床研究结果并不理想。我们研究的目的是确定治疗条件，在该条件下，N-甲基-D-天冬氨酸受体（NMDAR）拮抗剂美金刚对于酒精复发性行为可能产生更可靠的治疗效果。为此，对雄性Wistar大鼠进行训练，使其将几种离散刺激与乙醇给药联系起来。此后，一半动物接受一次简短的记忆重新激活训练，随后两次给予20mg/kg的美金刚，而另一半动物接受相同的治疗但没有记忆重新激活。之后，进行线索诱导的乙醇觅求行为测试，随后进行重复消退训练和重新习得测试。我们的数据表明，在线索诱导的乙醇觅求测试中，给予美金刚可减少与乙醇相关杠杆的反应。这种减少并不取决于在给予美金刚之前是否引入记忆重新激活训练。然而，在消退后，只有在短暂记忆重新激活训练后给予美金刚的组中，乙醇自我给药的重新习得受到损害，这表明这种给药方案对条件刺激与乙醇给药之间的关联产生了持久的破坏。总之，我们表明美金刚破坏了药物-线索关联，从而干扰了复发性行为，支持美金刚是酒精中毒治疗选择的可能性。我们的数据支持美金刚是酒精中毒治疗选择的可能性。然而，这种药物的有效性似乎在于其破坏条件行为的能力，并且应该与暴露于条件药物刺激相结合给予。
